Disteroidyl-ethers

ABSTRACT

BIOLOGICALLY ACTIVE DISTEROIDYL ETHERS OF THE FOLLOWING FORMULA ARE DISCLOSED:   17-(-C==C(==C-)-O-)ST   WHEREIN THE BROKEN LINE INDICATES THE PRESENCE OF A DOUBLE BOND IN THE 2&#39;&#39;(3&#39;&#39;) OR 3&#39;&#39;(4&#39;&#39;) POSITIONS; ST IS A STERIOD RESIDUE BELONGING TO THE ANDDROSTANE, 19-NOR-ANDROSTANE, GONANE AND 13-LOWER ALKYL GONANE SERIES; AND ST&#39;&#39; IS A STEROID RESIDUE BELONGING TO THE ANDROSTANE AND PREGNANE SERIES, AND THEIR 18-HOMO AND 19-NOR DERIVATIVES. THESE DISTEROIDS ARE PREPARED BY REACTING A CORRESPONDING 17-BHYDROXY STEROID OF SAID ANDROSTANE, 19-NOR-ANDROSTANE, GONANE AND 13-LOWER ALKYL GONANE SERIES WITH AN ENOLIZED OR ACETALIZED 3-KETOSTEROID OF THE ANDROSTANE, PREGNANE SERIES AND 18-HOMO AND 19-NOR ANALOGS THEROF, UNDER ANHYDROUS CONDITIONS AND IN THE PRESENCE OF AN ACID CATALYST.

United States Patent 3,803,182 DISTEROIDYL-ETHERS Alberto Ercoli, Milan, Rinaldo Gardi, Carate Brianza, and Romano Vitali, Casatenovo, Italy, assignors to Warner-Lambert Company, Morris Plains, NJ.

No Drawing. Filed Nov. 22, 1071, Ser. No. 201,243 Claims priority, application Italy, Nov. 24, 1970, 32,154/ 70 Int. Cl. C07c 169/20 US. Cl. 260-3974 40 Claims ABSTRACT OF THE DISCLOSURE Biologically active disteroidyl ethers of the following formula are disclosed:

wherein the broken line indicates the presence of a double bond in the 2(3') or '3(4') positions; St is a steroid residue belonging to the androstane, 19-nor-androstanc, gonane and 13-lower alkyl gonane series; and St is a steroid residue belonging to the androstane and pregnane series, and their 18-homo and 19-nor derivatives. These disteroids are prepared by reacting a corresponding 17-,8- hydroxy steroid of said androstane, 19-nor-androstane, gonane and 13-lower alkyl gonane series with an enolized or acetalized 3-ketosteroid of the androstane, pregnane series and 18-homo and 19-nor analogs thereof, under anhydrous conditions and in the presence of an acid catalyst.

GENERAL DESCRIPTION OF THE INVENTION The present invention relates to novel compositions of matter classified in the art of steroid chemistry as disteroidyl-ethers and to processes for their preparation. The disteroidyl ethers of this invention have valuable biological properties and consist of two steroid moieties joined together by an oxygen bridge which involves the carbon atoms in 17-position of a steroid moiety and the carbon atom in 3'-position of the other steroid moiety according to the partial structure:

wherein the broken line indicates the presence of a double bond in 2'(3') or 3'(4) positions.

The positions of the steroid moiety St are marked accordingly (i.e. C C C and so on) to distinguish them from the corresponding positions of the other steroid moiety St.

The steroid nucleus St, whose C is joined to the oxygen bridge, belongs to the series of androstane, 19-nor- The new disteroidyl-ethers of this invention are prepared by reacting a 17fl-hydroxy steroid of said androstane, 19-nor-androstane, gonane and 13-lower alkyl gonane series with an enolized or acetalized 3-ketosteroid of the androstane, pregnane series and 18-homo and 19- nor analogs thereof, or alternatively, by reacting an activated ether derivative of said 17/3-hydroxysteroid reagent with the corresponding 3-ketosteroid.

This reaction is carried out under anhydrous conditions, in the presence of an acid catalyst at temperatures between 50 C. and 200 C. for a period of from 30 minutes to 4 hours.

The term enolized or acetalized 3-ketosteroid is used herein to indicate the typical enolor acetal-derivatives, such as enol ethers, enol esters, hemiacetals or acetals of the 3-keto function, preferably alkyl enol ethers or dialkyl acetals of said 3-ketosteroid. The term activated ether derivative of 17B-hydroxysteroi means a steroid- 17 fi-yl enol ether, such as a l7-cycloalkenyl, and preferably a 17-cyc1opent-1'-enyl of said 17 3-hydroxy steroid.

Included among the preferred embodiments of the compositions of matter of this invention are compounds selected from the group consisting of disteroidyl ethers of the androstane-androstane series and androstane-pregnane series and the 18-homo and 19-nor analogs thereof reprcsented by the following structural Formulae I and H:

wherein the wavy line in 5, 5' and 16' position indicates that the hydrogen atom or the possible substituents may have the a or B configuration;

R represents hydrogen, a ketonic oxygen, an aor 1% hydroxy group, an aor fl-acyloxy group containing up to 10 carbon atoms or an aor p-alkoxy group whose alkyl consists of an aliphatic, cycloaliphatic or aromatic radical containing up to 10 carbon atoms;

R; and R represent each hydrogen or methyl;

R, and R represent each hydrogen or lower alkyl, such as methyl, ethyl, propyl and isopropyl;

R and R represent each hydrogen, hydroxy or ketonic oxygen, a methyl group or a chlorine atom when also- X represents chlorine;

R and Ry represent each hydrogen, an a-hydroxy group, free or esterified with an aliphatic acid containing up to 4 carbon atoms, a halogen atom, a lower alkyl or a lower alkylene radical, preferably a methyl or methylene radical;

R represents hydrogen, hydroxy or acyloxy group containing up to 10 carbon atoms;

R represents hydrogen, hydroxy, an acyloxy group containing up to 12 carbon atoms, a hydroxy group esterified with an inorganic oxygenated acid, or a halogen atom, particularly chlorine or fluorine;

X represents hydrogen or a halogen atom;

R and R or R and R may form together a new ring wherein R represents an alkyl radical containing up to 4 carbon atoms or an aryl and R represents an alkyl or alkoxy radical containing up to 4 carbon atoms or, alternatively, a ring consisting of a cycloalkyl group containing from 5 to 12 carbon atoms.

The carbon atom in 17' position of the Formula I may have one of the following structures:

H o wherein:

A represents hydrogen, an aliphatic, cycloaliphatic or aromatic radical containing up to 10 carbon atoms, an acyl radical containing up to 12 carbon atoms or the residue of an inorganic oxygenated acid;

B represents hydrogen or a saturated or unsaturated alkyl radical containing up to 4 carbon atoms inclusive, such as methyl, ethyl, propyl, butyl and their isomers, vinyl, allyl, allenyl, ethynyl, propynyl and butynyl.

The rings A and B may have one unsaturation between the carbon atoms in 1:2, 2:3, 4:5, :6, 5:10 positions; or two unsaturations between the carbon atoms in 1:2 and 4:5; or 4:5 and 6:7 positions.

In accordance with the nature of the reacting 3-ketosteroid, the rings A and B show one of the following structures:

1 ,V @Q/ (b) (c 4 The positions 7 and 7' may be further substituted by thioacyl groups and the position 1-2 and l' may carry a methylene bridge.

Also some 17'-spiro lactones of the 7'-acylthio-substituted compounds of Formula I fall Within the scope of this invention: substituted compounds in this group which are particularly interesting are those in which the 3-ketosteroid moiety consists of the l7-spiro-lactone of 3-keto- 7a-acetylthioandrost-4-ene and its 19-nor analog.

A further object of this invention is represented by those disteroidyl compounds in which the 3-keto-steroid moiety is aldosterone, 17-isoaldosterone and derivatives thereof.

The acyloxy and acyl radicals which are present in the Formulae I and II may be derivatives of organic and inorganic acids, particularly of organic saturated or unsatu' rated carboxylic acids (aromatic acids included) which may be formed by a straight or branched aliphatic chain, a cycloaliphatic, arylaliphatic or aromatic chain. They may also be substituted by alkoxy or amino groups, halogen atoms and the like. Typical esters are the acetate, propionate, butyrate, valerate, oenanthate, caproate and their isomers, the trimethylacetate, aminoacetate, hemisuccinate, hemimalonate, hemiphthalate, phenoxyacetate, phenylpropionate, phenylbutyrate, cyclopentylacetate, cyclopentylpropionate, cyclohexylacetate, fl-chloropropionate, laurate, benzoate, p.chloroor fluoro-benzoate, and the like.

Among the inorganic oxygenated acids, the sulfuric, phosphoric acids and salts thereof with alkali metals or organic bases are preferred.

The aliphatic, cycloaliphatic, arylaliphatic or aromatic radical containing up to 10 carbon atoms may be straight or branched, saturated or unsaturated and optionally substituted by functional groups.

Typical radicals are methyl, ethyl, vinyl, propyl, butyl, amyl, hexyl and their isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, benzyl, p.chlorobenzyl, l-methoxycyclopentyl, l-ethoxycyclopentyl, lmethoxycyclohexyl, l-ethoxycyclohexyl, tetrahydropyranyl, and the like.

The new disteroidyl ethers of this invention exhibit improved and/or increased hormonal properties as compared with those possessed by the two steroid entities. This means that the resulting properties in the new compounds are not merely a sum of the activities of the two individual steroid moieties since the disteroidyl compounds show a degree of activity and a biological behavior which are dilferent from those shown by a simple mixture of the two constituting steroids.

In particular, the disteroidyl ethers of Formula I wherein the C carbon atom has the structure (B being hydrogen or lower alkyl) are andro-anabolic agents having a more favorable anabolic/ androgenic ratio or a higher anabolic activity as compared with that resulting from the two component steroids. Therefore, the new compounds may be advantageously used in place of androgenic or anabolic agents used in known pharmaceutical preparations. They may be orally or subcutaneously administered to patients, the route and dose varying with the nature and the severity of the symptoms to be treated. Typical derivatives of this class of compounds include: 17p-( 17'B-propionoxy-19'-nor-androsta-3 ,S'-dien-3'- yloxy) l9-norandrost-4-en-3-one, 17p-( 17fl-benzoyloxy-19-norandrosta-3',5'-dien-3'- yloxy) l9'-norandrost-4-en-3 -one, 17,8- 17f3-phenylpropionoxy-19'-norandrosta-3 ',5'-

dien- '-yloxy)-l9-norandrost-4-en-3-one, 17B- 17 'B-lauryloxy- 19-norandrosta-3',5'-dien-3 yloxy)-19-norandr0st4-en-3-one,

17B- 17'fi-hydroxy-l9'-norandrosta-3',5'-dien-3 yloxy)-19-norandrost-4-en-3-one and the corresponding 17-hemisuccinate thereof.

These compounds show a prolonged anabolic activity after single injection which is much higher than that shown by the single parent steroids. They also possess a much more advantageous anabolic/androgenic ratio and show high anabolic activity also when orally administered.

The comparison carried out between 175-(17'B-propionoxy-l9-norandrosta-3',5'-dien-3-yloxy) 19 norandrost-4-en-3-one and the well known 17;3hydroxy-estr- 4-en-3-one decanoate (which is one of the most active anabolic agents) proved that at the same dose, l7B-(l7'fipropionoxy-19'-norandrosta 3',5 dien-3-yloxy)-l9- norandrost-4-en-3-one shows a higher anabolic activitydeduced from the weight of the muscle levator aniand a much lower androgenic activity-deduced from the weight of the seminal vesicles-than the reference compound.

The new disteroidyl ethers of Formula I wherein the C carbon atom has the structure (B being a lower alkenyl or alkynyl radical, i.e. 17avinyl, allyl, allenyl, ethynyl, propynyl and the like) and those disteroidyl ethers deriving from a progesterone moiety (i.e. compounds of Formula H wherein R is hydrogen and R is hydrogen, hydroxy or acyloxy) possess improved and increased progestational activity and exhibit anti-conceptional properties. In addition, these new classes of compounds show anti-uterotrophic, antihypophysis and estrogenic actions to a certain extent, but these side-activities, which are usually connected with a progestinic activity, are exhibited in a different degree as compared with the total activity of the progestational entity or entities incorporated in the disteroidyl com pound.

This is particularly evident in compounds such as 17;8-(17'oi-acetoxy-20'-oxopregna-3 ,5-dien-3-yloxy) 5a-androstan-3-one, 17 8-(17'fl-acetoxy-l9'-nor-17'a-pregna-3',5-dien-20'- yn-3-yloxy)-androst-4-en-3-one, 17,8- l7 3-acetoxy-l9'-nor-17' x-pregna-3',5 '-dien-20'- yn-3'-yloxy)-estr-5-en-3-ol acetate, 17 ;8-( 17'a-acetoxy-20-oxo-6'-methylpregna-3',5'-dien -yloxy)-l9-nor-androst-4-en-3-one, and 17/3- l7,B-acetoxy-l9-nor-17a-pregna-3',5'-dien-20'- yn-3'-yloxy)-estr-4-en-3-one.

These compounds show a remarkable increase of progestational activity in comparison with the activity displayed by the progestational moiety and in addition show a lower antigonadotrophic action.

Thus, they are useful therapeutic agents having nearly pure progestational activity and for this reason can be advantageously used for the treatment of physiological disorders in female animals and in women in similar manner as known progestins, e.g. progesterone, ethisterone and the like.

It is also to be pointed out that all disteroidyl ethers of the above classes have a biological behavior (evaluated as to the antiuterotropic and antihypophysis activity, as well as the activity on the reproductive physiology) which generally differs from that shown by the mixture of the two component steroids.

The disteroidyl ethers of Formula II above (wherein R is other than hydrogen) possess cortical activity and exhibit increased and prolonged anti-inflammatory activity. Of particular interest and importance are compounds which incorporate a cortical moiety deriving from llB-hydroxycorticosteroids, such as hydrocortisone, prednisolone, their 6a-halo or Got-methyl derivatives, their 9a-fluoro or 9oz-Chl010 analogs, betamethasone, dexamethasone, 9OL-flUOI'O 16-methylene prednisolone, and corresponding 17-esters and/or 2l-esters thereof, and from the corresponding ll-keto and ll-dehydro analogs of the foregoing 11 fl-hydroxy compounds.

The new disteroidyl ethers belonging to the class of corticoids possess potent anti-inflammatory activity and are used for the treatment of inflammatory conditions in the same manner as known corticoids. Thus they may be administered by intracutaneous or intramuscular route in aqueous suspension or in aqueous solution when the corresponding 2l-hemisuccinate alkali metal salt is used. They may also be administered orally in the form of tablets, capsules or syrups (in aqueous or non-aqueous suspensions), or topically as creams, lotions or in the form of ophthalmic suspensions. In each instance the pharmaceutical preparations are prepared according to procedures well known in the art.

In general the pharmaceutical formulations of our disteroidyl ethers corresponding to Formulae 'I and II are prepared and administered utilizing procedures known in the art.

DETAILED DESCRIPTION OF THE PROCESS According to the present invention the process for the preparation of the preferred new disteroidyl ethers of Formulae I and II consists in reacting a -hydroxy steroid of the androstane, 19-nor-androstane, gonane and 13-lower alkyl gonane series (III) under anhydrous conditions, in a suitable solvent such as for example benzene, toluene, dimethylformamide and isooctane, and in the presence of a suitable acid catalyst-such as for example p-toluenesulfonic-, naphthalenesulfonic acid, pyridine p-toluenesulfonate, pyridine chlorhydrate and the likewith an enolized or acetalized 3-ketosteroid of the androstane, pregnane series and their 18-homo or 19-nor analogs (1V or V), at a temperature between 50 C. and 200 C., preferably at a temperature higher than 70 C., for a period of from 30 minutes to 4 hours.

In alternative, the compounds of the invention may be also prepared by reacting, instead of the l7B-hydroxy steroid of the said androstane, 19-norandrostane, gonane and 13-lower alkylgonane series, an activated ether derivative thereof with the 3-keto steroid of the androstane, pregnane series and their l8-homo or 19-nor analogs.

In the above formulae there are present all the possible substituents cited for the Formulae I and II; the rings A and B of the Formulae VI and VII have one of the structures (a)(e) and the substituents R, R R 1, R R R R R R R R X and the atom C have the abovesaid meaning with the exception that R is never a free hydroxy group and A is never hydrogen. In order to obtain those compounds in which R is a free hydroxy group and in the carbon atom C A is a hydrogen atom, the compounds of Formulae VI and VII may be submitted to alkaline hydrolysis.

The present invention includes all those compounds which may be obtained through obvious reactions, such as saponification which may be carried out on any possible acyloxy group present in the disteroidyl compound; acylation or etherification, by which a desired acyloxy or an ether group may be introduced in place of a free hydroxy group and alkylation generally carried out by means of an appropriate alkyl magnesium halide.

The structure of the disteroidyl derivative obtained through the etherification of a 17fi-OXY-a11dr0st3ne or 19- nor-androstane (III) with a keto-steroid (IV or V) strictly depends from the nature of the steroid itself. The following scheme is given:

alkyl orthoformiate and of the corresponding alcohol over the 3-ketone according to Serini and Kosters method (Ber. 71, 1766; 1938). The enol ethers of saturated 3- keto steroids or may also be obtained by reacting the 3-keto steroid with methanol in the presence of an acid catalyst, according to the method of M. Janot et al.; (Bull. Franc. 2109, 1961) or to the method of J. Slomp et al. (J.A.C.S. 77, 1216, 1955).

By submitting a dialkyl acetal of the saturated 3-ketone to pyrolysis under analogous conditions to those disclosed by H. H. Inhofr'en and Coll. (Ann. 568, 52, 1950), the corresponding enol ether is obtained. It will have the structure: (a) A ene, Set if the 4-keto steroid belongs to the series 50:, or the structure (b) A -ene-5fi if the 3- keto belongs to the series 55.

The enol ethers of 3-keto-5a-steroids having a A -ene structure may be obtained, according to the method described in our U.S. Pat. No. 3,118,917, by catalytic hydrogenation of the double bond in 5-position from the corresponding enol ethers of analogous A -3-ketones (that is ethers of 3-OXY-A- -diCIK: steroids), followed by spontaneous migration ofthe remaining double bond from the 3 :4 position to the 2:3 position.

The enol ethers of 3-keto Six-steroids having a A -ene structure may be obtained, according to the method described in our U.S. Pat. No. 3,264,329, by catalytic hydrogenation of the corresponding enolethers of A -3-ketosteroids in the presence of a catalytic amount of a basic substance.

(c) and (c') The enol ethers of A -3-keto-5a-steroids haying the A -diene structure may be obtained by submitting the triethers of 1a,3,3-trihydroxy-5a-steroids to pyrolysis as described in British Pat. No. 1,203,278 and as disclosed and claimed in the U.S. Pat. application Ser. No. 830,841 filed June 5, 1969.

The pyrolysis reaction is preferably carried out at a temperature of from C. to 155 C., in the presence of a suitable acid catalyst.

The triethers of 1a,3,3-trioxysteroids starting materials are in their turn prepared by the process disclosed and claimed in the U.S. Pat. No. 3,475,467. They may be obtained by treating the A -3-keto-5a-steroids with an alcohol and an orthoformiate under anhydrous conditions at a temperature lower than 60 C. in the presence of an acid catalyst.

According to the process of the present invention, both 1a,3,3-trialkoxys teroids and the corresponding A -3-keto enol ethers may be used for the condensation reaction with the l7 3-hydroxy steroid but the formers, being the precursors of the enol ethers, have the advantage of a more immediate preparation and therefore may be preferred starting materials for the preparation of the disteroidyl derivatives having a A -diene structure.

(d) The enol ethers of A -3-ketones may be easily pre- Structure of the rings A and B in the disteroidyl Parent 3-keto compound Enolethers or acetals starting materials compound 5 d enol ether.-- B-keto-fia-steroid acetal ga 5% k i g-s t r i 34mmbstem] B-ketdSfl-steroid acetal. (b) a 5 Al.3.ket .5 m 1a-81k0XY-3-k6t0-5a-Stel0ld acetal (e) A -diene, 5a.. A -3-keto-5fi-steroid 1a-a1k0xy-3-keto-5fl-stero1d acetal (e) Ah -dime, 55, A -3-keto steroid -4t-keto-steroid enol ether A -d1ene steroid.

Preparation of the starting materials (a) and (b) The acetals of saturated 3-ketones (so: or 513) may be easily prepared by simultaneous action of an (e) A -triene.

pared by submitting the A -3-ketosteroid to enol etherification with an alkyl orthoformiate or an alcohol, according to well known procedures of the art.

When, as reagent material in the method of the present invention, there is used an enol ether of a A -3-ketone containing a higher alkyl radical than methyl or ethyl, the method disclosed in our U.S. Pat. No. 3,019,241 may be applied to the preparation of such reacting materials. This method consists in submitting the methylor ethyl-enol ether to trans(enol)-etherification by treatment with a higher alcohol.

(e) The 3-enolethers of 3-keto-A -steroids may be obtained by enol-etherification of the 3-keto A -pregnadiene with ethyl orthoformate and an alcohol in the presence of a strong acid catalyst as described in the US. Pat. No. 3,068,253. In place of the 3-eno1ethers of 3-keto-A -steroids there may be used, for the preparation of the disteroidyl compounds having a A triene structure, the corresponding alkyl enol ethers of la-alkoxy-A' -3-ketones (or la,3-alkoxy-A -dienes). These compounds are obtained by submitting the A -3-keto-steroids to the simultaneous action of an alkyl orthoformiate and of the corresponding alcohol under anhydrous conditions at a temperature lower than 60 C., in the presence of a suitable acid catalyst.

The method for preparing 1a,3-dialkoxy-A -diene steroids of the pregnane series is disclosed in our US. Pat. No. 3,506,650. This method may be applied to the preparation of corresponding 1a,3-dialkoxy-A -diene steroids of the androstane series and of their 19-nor or l8-homo derivatives.

The following examples are given to illustrate the invention without limiting it.

In order to make easier the description of the preparation of a number of compounds of the invention, the reacting starting steroids of all examples have been listed in two separated Tables A and B and marked by a progressive number following the letter A or B. In Table A are listed the 17-hydroxy steroids or activated derivatives thereof, and in Table B are listed the 3-keto-steroids or their corresponding enol ethers or ketals.

TABLE A 17B-hydroxy-5u-androstan-3-one. 17/3-hydroxy-513-androstan-3-one. 17,8-hydroxy-5a-androstan-1-en-3-one. l7fi-hydroxyandrost-4-en-3-one. 17/8-hydroxyandrosta-1,4-dien-3-one. 5a-androstane-3fl,l7fi-diol 3-acetate. 5m-androstane-3a,17;3-diol B-acetate. 5fi-androstane-3a,17fl-diol S-acetate. 5a-androst-1-ene-3B,17fl-diol 3-acetate. Androst-5-ene-35,17 8-dio1 3-acetate. 5a-androst-2-en-l7B-ol. 17fi-hydroxyester-4-en-3-one. 17,3-hydroxy-l-methyl-Su-androst-l-en-3-one. 14 Estr-4-ene-3B,17 8-dio1 3-acetate. 17fl-hydroxy-5a-estran-3-one.

16 17fi-hydroxygon-4-en-3-one.

5a-androstane-3a,17 8-diol S-enanthate. 17,8-cyclopent-1-enyloxy-androst-5-en-3fl-ol acetate. 19 3a-methoxy-5a-androstan-17fl-ol.

TABLE B 3,3-dimethoxy-5a-androstan-173-01 acetate. 3,3-dimethoxy-5p-androstan-17,8-01 propionate. 1,3,3-trimethoxy-5u-androstan-17 3-01 acetate. 3-methoxy-1-methyl-5a-androsta-1,3-dien-l7,3-01

acetate. 3-ethoxyandro sta-3,5-dien-17-one. 3-ethoxyandrosta-3,5-dien-17 8-01 acetate. 3-ethoxyandrosta-3,5-dien-175-01 propionate. 3-ethoxyandrosta-3,5-dien-17p3-ol p-cyclopentylpropionate. 3-ethoxyandrosta-3,5-dien-l7fl-ol benzoate.

S-ethoxy-17a-methylandrosta-3,5-dien-17p-ol acetate. 3-ethoxy-9u-fluoro-l7a-methylandrosta-3,S-diene- 115,17/3-diol acetate. 3-ethoxyestra-3,5-dien-17-one. 3-ethoxyestra-3,5-dien-1718-01 acetate. 3-ethoxyestra-3,5-dien-17,8-01 propionate. 3-ethoxyestra-3,5-dien-17fl-ol laurate. 3-ethoxyestra-3,5-dien-175-01 p-phenylpropionate. 3-ethoxyestra-3,5-dien-17fi-o1 benzoate. 18 3,3-dimethoxy-5a-pregnan-ZO-Qne.

1 0 3,3-dimethoxy-SB-pregnan-ZO-one. 3,3-dimethoxy-5p-pregnan-1 1,20-dione. 3,3-dimethoxy-1lfi-hydroxy-5fl-pregnan-20-one. 3,3-dimethoxy-21-hydroxy-SB-pregnan-ZO-one acetate. 3,3-dimethoxy- 17 a-hydroxy-SB-pregnane-l 1,20-

dione acetate. 1,3,3-trimeth0xy-5a-pregnan-2-0-one. 1,3,3-trimethoxy-17a-hydroxy-sa-pregnan-20-one acetate. 3-ethoxypregna-3,5-dien-20-one. 3-ethoxy-17a-hydroxypregna-3 ,5 -dien-20-one acetate. 3-ethoxy- 17 a-hydroxy-6-methylpregna-3 ,5-dien-20- one acetate. 3-ethoxy-17a-hydroxy-6-chloropregna-3 ,5 -dien-20- one acetate. 3ethoxy-17a-hydroxy-16-methylenepregna-3,5-dien- 20-one acetate. 3-ethoxy-16a,17a-(l'-methylbenzylidenedioxy)- pregna-3,5-dien-20-one. 3-ethoxy-6a,2l-dimethyl-l7a-pregna-3,5-dien-20- yn-17fl-ol acetate. 3-ethoxy-19-norpregna-3,5-dien-20-one. 3-ethoxy-17a-hydroxy-19-norpregna-3,5-dien-20-one acetate. 3-ethoxy-17a-hydroxyl9-norpregna-3,5-dien-20-one n.hexanoate. 3-ethoxy-17a-methylestra-3,5-dien-175-01 acetate. 3-ethoxy-19-nor-17a-pregna-3 ,5-dien-17 8-01 acetate. 3-ethoxy-19-nor-17m-pregna-3 ,5-dien-20-ynl7fl-ol acetate. 3-ethoxy-21-methylene-l9nor-17a-pregna-3,5,20-

trien-l7fl-ol acetate. 3-ethoxy-2 1-ethynyl-19-nor-17a-pregna-3,5-dien-20- yn-17B-ol acetate. 3-ethoxy-1Zip-ethyl-17a-ethynylgona-3,5-dien-1713-01 acetate. 3-ethoxy-l711,21-dihydroxypregna-3,S-diene-1 1,20-

dione 2l-acetate. 3-ethoxy-1 1p,17u,21-trihydroxypregna-3,5-dien-20- one ZI-acetate. 3-ethoxy-9u4iuoro-1 118,17a-21-trihydroxypregna- 3,5-dien-20-one 21-acetate. 3-ethoxy-9ot-fluoro-1 1,8, :,21-tlihYdI'0XY-16fimethylpregna-3,5-dien20-one 21-acetate. 3-ethoxy-17a,21-dihydroxypregna-3,5-diene-1 1,20-

dione 2 l-acetate. 1a,3-dimethoxy-17a,2l-dihydroxypregna-3,S-diene- 1 1,20-dione ZI-acetate. 3-methoxy-11p,l7u,2l-trihydroxypregna-1,3,5-trien- 20-one 2l-acetate. 3-methoxy-9u,1lfi-dichloro-17a,21-dihydroxypregna- 1,3,5-trien-20-one ZI-acetate. 3-methoxy-9w,1lp-dichloro-17u,21-dihydroxy-16umethylpregna-1,3 ,5-trien-20-one 2 l-acetate. 3-meth0xy-9a,1 lfi-dichloro-17a,21-dihydroxy-16 3- methylpregna-1,3,5-trien-20-one 21-acetate. 3-methoxy-9a-fluoro-11B,17a,21-trihydroxy-16amethylpregna-1,3,5-trien-20-one 21-acetate. 3-methoxy-9a-fluoro-11p,17a,21-trihydroxy-16umethylpregna- 1,3 ,5-trien-20-one 17,21-diacetate. 3-methoxy-9a-fluorol7oc,2 l-dihydroxy- 1 Got-methylpregna-1,3 ,5-triene-l1,20-dione 17,21-diacetate. 3-methoxy-9a-fluoro-11;9,17a,21-trihydroxy-l6pmethylpregna-1,3 ,5-trien-20-one 21-acetate. 3-methoxy-9wfluoro-l 1,3, l7w,21-trihydroxy-16 3- methylpregna-1,3,5-trien-20-one 17,21-diacetate. 3-methoxy-9a-fluoro-17a,21-dihydroxy-16/3-methylpregna-1,3,5-triene-11,20-dione 21-acetate. 3-methoxy-9a-fiuor0-17u,21-dihydroxy-l6B-methylpregnal,3,5-triene-l1,20-dione 17,21-diacetate.

B 59 3-meth0xy-9a-fiuoro-1 113, 17a,21-trihydroxy-16- methylenepregna-1,3,5-trien-20-one 21-acetate.

B 3-methoxy-9a-fluoro-17,21-dihydroxy-16-methylenepregna-1,3,5-triene-11,20-dione 17,21-diacetate.

B 3-methoxy-9a-fluor0-1 1,8,21-dihydroxy-16a,17a-isopropylidenedioxy-pregna- 1,3 ,5 -trien-20-one 21-acetate.

B 3-methoxy-9a-fiuoro-16oz,l7a-isopropylidenedioxy- 21-hydroxypregna-1,3 ,5 -triene-1 1,20-dione 21-acetate.

B 3-ethoxy-6wfiuoro-1 1,8,21-dihydroxy-16a,17m-isopropylidenedioxy-pregna-3,S-dien-ZO-one 21-acetate.

B 3-methoxy-6u-fluoro-16u,17a-isopropylidenedioxy- 21-hydroxypregna-1,3,5-triene-1 1,20-dione 21-acetate.

B 3-methoxy-6wfiuoro-11(3,21-dihydroxy-16a,17u-isopropylidenedioxypregna-1,3,5-trien-20-one 21-acetate.

B 3-methoxy-6a,9a-difiuoro-1 1B,17a,21-trihydroxypregna-1,3,5trien-20-one 17,21-diacetate.

B 3-methoxy-6a,9a-difluoro-170;,2l-dihydroxypregna- 1,3,5-triene-11,20-dione 21-acetate.

B 3-methoxy-6m,9a-difiuoro-17m,21-dihydroxypregna- 1,3,5-trien-11,20-dione 17,21-diacetate.

B 3-methoxy-6a,9 a-difiuoro-l 1B,17a-dihydroxypregna- 1,3,5-trien-20-0ne propionate 1 B- 3-methoxy-6a,9adifluoro-17a-hydroxypregna-1,3,5-

triene-11,20-dione propionate.

B 3-ethoxy-1 1fl,18-oxido-18,21-dihydroxypregna-3,S-

dien-ZO-one 18-benzoate 2l-acetate.

B 3-ethoxy-21-hydroxypregna-3,S-dien-ZO-one acetate.

B 3-ethoxy-17u-pregna-3,5-dien-21,17fl-carbolactone.

B 3-ethoxy-7a-mercapto-17u-pregna-3,5-diene-21.175-

carbolactone acetate.

B S-ethoxy-19-nor-17a-pregna-3,5-diene-21,17 3- carbolactone.

B 3-ethoxy-7a-rnercapto-19-nor-17a.pregnaP3,5-diene- 21, 17 p-carbolactone acetate.

B 4,5-dihydrospiro-3-ethoxy-[androsta-3,5-diene-17,

2'(3',4)-furane]-7u-thiol acetate.

B 3,3-dimethoxy-17a-hydroxy-SB- regnan-ZO-One acetate.

B 3-eth0xy-1lp-methyl-19-nor-17a-pregna-3,S-dien-ZO- yn-l'ifl-ol.

B 3-methoxy-6a-fluoro-2l-hydroxy-l6a-methylpregna- 1,3,5 -trien-1 1,20-dione 21-acetate.

B 3-methoxy-6a-fluoro-l1,21-dihydroxy-16a-methylpregna-l,3,5-trien-20-one ZI-acetate.

B 17B-hydroxyestr-4-en-3-one acetate.

B 17fi-hydroxy-5a-androstan-li-one propionate.

EXAMPLE 1 1713- 1 1 ,20'-dioxo- 17 'a-hydroxy-21 -acetoxypregna- 3,5 '-dien-3 '-yloxy -andrst-4-en-3-one grams of cortisone ZI-acetate 3-ethyl enol ether (B were added to a boiling solution of 5.5 g. testosterone (A and 60 mg. pyridine p-toluenesulfonate in 5000 ml. toluene. The mixture was refluxed and the solvent distilled for about 40 minutes, then 0.6 ml. pyridine were IEreparation of corresponding 3-keto-A- steroid is carried out as follows: 10 g. of 611,9a-difluoroprednisolone 17- propionate, described in British Pat. 1,202,001 Example 1, are dissolved in 100 ml. Pyridine: methylene chloride (1: 1), cooled to 0 C. then g. of p.toluenesulfonic aciddissolved in 100 ml. pyridine :methylene chloride (1 :1) are added and the mixture is allowed to rest overnight at 0.5" C. 6a,9a-difiuoro-llB,17a.,21-trihydroxypregna-1,4-diene 17-propionate 21- tosylate melting at 205-207 C. thus obtained is dissolved in acetone, treated with g. sodium iodide, refluxed for 24 hours; then 32, 75 ml. acetic acid are added and further refluxed for one hour. The mixture is diluted with a 10% aqueous sodium acid sulfite, concentrated under vacuum and extracted with methylene chloride. Removal of the solvent followed by recrystallization from methylene chloride ether afforded 7.4 g, of 6a,9a-diflu0ro-11fi,17a.-dihydr0xy-1,4-diene-3, ZO-dtone 17-propionate melting at 235-237 C.

added and the solvent was completely removed, under re duced pressure.

The residue, taken up with methanol and filtered, gives 6.2 g. 1718-(11',20'-dioxo-17'rx-hydroxy-21-acetoxypregna- 3,5'-dien-3'-yloxy)-androst-4-en-3-one, melting at 250- 255 C. By further recrystallization from methylene chloride-methanol a melting point of 265--268 C. was obtained; [a] =+38 (c.=l%, dioxane).

In accordance with the above procedure the following disteroidyl ethers are obtained.

methylpregna-1',3',5trien-3-yloxy)-androsta- 1,4-dien-3-one.

EXAMPLE 26 17/3-(17'fi-acetoxy-S'a-androsta-1,3 '-dien-3 '-yloxy) androst-5-en-3fi-ol acetate 4 grams of 1,3a,3,8-trimethoxy-Sa-androstan-1713-01 acetate (B were added to a boiling solution containing 4 g. 3B-acetoxyandrost-5-en-173-01 (A and mg. pyridine p-toluenesulfonate in 1500 ml. benzene. The mixture was refluxed and the solvent distilled for minutes. Then some drops of pyridine were added and the solvent was completely removed under reduced pressure.

The residue was taken up with methanol, filtered and crystallized from methylene chloride-methanol to give 4.36 g. 17,6-(17'y8-acetoxy Sa androsta-1',3'-dien-3'-yloxy)- androst-S-en-Iifi-ol acetate, melting at 223-229 C. By further recrystallization from the same mixture of solvents, 3.7 g. of product melting at 230233 C. were obtained: [a] =--8 (c.=l%,dioxane).

In accordance with the above procedure the following disteroidyl ethers are obtained.

AFI'BBI And- 51 EXAMPLE 84 17 8- 17'13-propionoxy-5 -u-androst-2'-en-3 '-y1oxy) androst-S-en 35-01 acetate A mixture of 5 g. androstanolone 17 propionate 3,3- dimethylacetal (B and 5 g. 3fi-acetoxyandrost-5-en-175- 01 (A1 in 30 ml. dimethylformamide was treated with p-toluenesulfonic acid and then heated on an oil bath to -150 C. for 40 minutes and to ISO-200 C. for 20 minutes. Then some drops of pyridine were added, the solvent completely removed under reduced pressure, and the residue taken up with methanol, filtered and crystallized from methylene chloride-methanol to give 5 g. 173- (17'B-propionoxy-5a-androst 2' en-3'-yloxy)-androst- 5-en-3B-ol acetate, melting at 224-226 C.; [ah- +3 (c.=1%, dioxane).

In accordance with the above procedure the following disteroidyl ethers are obtained.

EXAMPLE 94 17/3-( 17'13-acetoxyestra-3,5'-dien-3 '-yloxy) -androst-5-en 3 9-01 acetate A mixture of 2 g. 1713-(cyclopent-1'-enyloxy)-androst- 5-en-3B-ol acetate (A and 2 g. 19-nortestosterone acetate (B in 20 ml. dimethylformamide was treated with 20 mg. p-toluenesulfonic acid and then heated on an oil bath to 120-150 C. for 40 minutes and to ISO-200 C. for 30 minutes. During this last period, the reaction mixture was bubbled with a light nitrogen stream, then a few drops of pyridine were added and the solvent was removed under reduced pressure and the residue taken up with methanol and filtered to give 1.28 g. 17,8-(17'fi-aoetoxyestra-3',5'-dien-3-yloxy)-androst-5-en-3fiol acetate, meltting at 220-226 C. By further recrystallization from methylene chloride-methanol 1.1 g. of the compound having a melting point of 230-233 C. was obtained; [a] 113 C. (c.=l%, dioxane).

In accordance with the above procedure the following disteroidyl ethers are obtained.

12 grams of 19-nortestosterone 17-propionate 3-ethyl enol ether (B were added to a boiling solution of 12 g. l9-nortestosterone (A and 0.8 g. pyridine p-toluenesulfonate in 9 1. toluene. The mixture was refluxed and the solvent was distilled for about 55 minutes. Then 1 m1. pyridine was added and the solvent completely removed under reduced pressure. The residue was taken up with methanol and filtered to give 16.35 g. 17p-(17'ppropionoxyestra-3,5'-dien 3' yloxy)-estra-4-en-3-one, melting at 177-184 C. By further recrystallization from ethylene chloride-ethanol a melting point of 185-188 C. was obtained; ['a] ='9'1.5 (c.'=1%, dioxane).

:In accordance with the above procedure the following disteroidyl ethers are obtained.

1 gram of 17B-(1713-propionoxyestra-3'-5'-dien-3'-yloxy) -estr-4-en-3-one (-Ex. 97) in 50 ml. methanol and 25 ml. methylene chloride was added to 7 ml. of a ethanolic potassium hydroxide solution and refluxed for 4 and a half hours in nitrogen atmosphere. After con- 16 centration under reduced pressure the mixture was poured into water to obtain 17fi-(17fi-hydroxyestra-3,5'-dien-3'- yloxy)-estr-4-en-3-one as white solid which, recrystallized from ethylene chloridemethanol, melts at 250-253" C.; [a] (c.'- 1%, dioxane).

In accordance with the above procedure the following disteridyl ethers are obtained.

EXAMPLE 129 17 6- 17'fi-hydroxyestra-3',5-dien-3'-yloxy)-estr-4-eu- 3-one sulfate, sodium salt In a flask provided with a stopper, 9.4 ml. anhydrous pyridine and 0.42 ml. acetic anhydride were added to 0.731 g. anhydrous sulfate pyridine and the mixture was stirred for 30 minutes. A solution of 1 g. 17e-(I7'p-hydroxyestra 3',5' dien 3' yloxy)estr 4 en 3 one in 10 ml. pyridine was added and the mixture kept under stirring overnight at room temperature. The contents of the flask were evaporated under reduced pressure at 40 C. and the residue was taken up with water, adjusted to a pH 11-12 with a 5% aqueous solution of sodium hydrate and extracted with successive portions of n.butanol. Then butanol was removed by a short heating and the residue, taken up with ether, gives 1 g. (17'5 hydroxyestra- 3',5-dien-3'-yloxy)-estr-4-en-3-one sulfate crude sodium salt which can he purified from methane-ethyl ether; [u] =-82.6 (c.=1%, ethanol 95 In accordance with the above procedure the following disteroidyl ethers are obtained.

EXAMPLE 134 175-( l7'fl-Hemisuccinoxyestra-3,5'-dien-3'-yloxy)- estr-4-en-3-oue A solution of 3 g. 17B-(I7'fi-hydroxyestra 3',5' dien- 3-yloxy)-estr-4-en-3-one (BX. 117) was treated with 9 g. succinic anhydride and kept at 60 C. for 48 hours. The mixture was poured into ice-water and the product precipitated by addition of diluted hydrochloric acid. EX- traction with ether gave, after removal of the solvent under reduced pressure and recrystallization of the residue from ether, 2.85 g. of 1713-(17'p-hemisuocinoxyestra- 3,5'-dien-3'-yloxy)-estr-4-en-3-one, melting at 175+1SQ []D=' 89 (-=1%, diQXd1l@)- In accordance with the above procedure, using phthalic anhydride or succinic anhydride, the following disteroidyl ethers are obtained.

succinate. Ex. 126.

EXAMPLE 15 1 A solution of 5 g. 17B-(17'-oxoandrosta-3', '-dien-3'- yloxy)-androst-5-en-3fi-ol acetate. (Ex. 11') in 100 ml. anhydrous tetrahydrofuran was added to 200 ml. of tetrahydrofuran solution of methylmagnesium bromide prepared from 20 g. magnesium and 100 g. methylbromide. The mixture was refluxed for 6 hours and then decomposed with satured ammonium chloride. Extraction with ether, followed by removal of the solvents under reduced pressure, and recrystallization of the residue from methylene chloride-acetone, afforded 3.5 g. of crystals of 176- (17'5 hydroxy 17u methylandrosta 3',5' dien-3'- yloxy)-androst 5 en-3 8-ol, melting at 232235 C., [a] =-74.5 (c.=1%, dioxane).

In accordance with the above procedure using a suitable alkylmagnesium halide, following disteroidyl ethers are obtained.

Preparation trom- End-product Ex. 52.

End-product Ex. 91 plus Brlfi/IgCHr- Ex. Name 18 EXAMPLE 15s A solution of 1.86 g. of 17/3-(9'a-fiuoro-11',20'-dioxo- 17 'a-hydroxy-21-acetoxy 16'18 methylpregna 1',3,5' trien-3'-yloxy)-estr-4-en-3-one (Ex. 55) in ml. of tetrahydrofuran and 90 ml. of methanol kept under nitrogen, was treated with 1.86 ml. of 1 M methanol solution of sodium methoxide. After stirring at room temperature for-20 minutes, the solvent was evaporated under reduced pressure and the residue taken up with water and filtered. A crystallization from methylene chloride-methanol gave 1.24 g. of crystals of l7fi-(9'a-fluoro-11,20'-dioxo-17m, 21 dihydroxy 1673 methylpregna 1',3',5'-trien-3'- yloxy) estr 4 en 3 one, melting at 259-262 C. [m] =68 (c.=1%, dioxane).

In accordance with the above procedure the following disteroidyl ethers are obtained.

EXAMPLE 172 176 (9'a-fluoro 11',20-dioxo-17'u-hydroxy-21'-hernisuccinoxy 166 methylpregna-1,3',5'-trien-3-yloxy)- estr-4-en-3-one A solution of 1.4 g. of 17/3-(9'-a-fluoro-l1',20'-dioxo- 17 'oc,21' dihydroxy-16'B methylpregna-1',3, -trien-3'- yloxy)-estr-4-en-3-one (Ex. 158) and 4.2 g. of succinic anhydride in 42 ml. of pyridine was kept overnight at room temperature. The mixture was then poured into 500 ml. of saturated salt solution and extracted with ether. The organic layer was separated, dried on anhydrous sodium sulfate and the solvent removed under reduced pressure. The residue was crystallized from methylene chloride-methanol to give 940 mg. of crystals of 17B-(9'ozfluoro 1l,20' dioxo-17'a-hydroxy-2l'-hemisuccinoxy- 1 6'B-methylpregna-1',3',5'-trien-3'-yloxy)-estr-4-en-3-one, melting at 197-201 C. (dec.), [a] =-44 (c.=1%, dioxane).

19 In accordance with the above procedure, using phthalic anhydride or succinic anhydride, the following disteroidyl others are obtained.

End-product End-product End-product End-product End-product End-product EXAMPLE 184 171M17'B-hydroxy-5'u-androst-2-en-3'-yloxy)- a-androstan-3-one EXAMPLE 191 To a solution of 2 g. 17fl-( 17'a-acetoxy-20'-oxo-6'- methylpregna 3',5'-dien-3-yloxy)-estr-4-en-3-one (Ex. 13) in 30 ml. tetrahydrofuran, 0.4 g. sodium borhydride in 2 ml. water was added. After keeping overnight at room temperature under occasional stirring, the solvent was removed under reduced pressure, then Water was added and the product recovered by filtration. Recrystallization from methylene chloride-methanol afforded pure 1713 (17flat-acetoxy-ZO'-OX9-6'-mcthylpregna-3,5'-dien-3'- yloxy) -estr-4-en-3fi-0l.

In accordance with the above procedure the following disteroidyl ethers are obtained.

EXAMPLE 1 9 6 H S-(9'04 fluoro 11',20'-dioxo-17'a,21'-dihydroxy-l6',B- methyl-pregna 13',5' trien-3'-yloxy)-5m-androst-1- en-3-one 21-disodium phosphate To a solution of 0.1 ml. of redistilled phosphorus oxychloride in 5 ml. of pyridine is added at --25 C. With stirring a solution of 400 mg. of 17B-(9a-liuor0-11,20- dioxo 17' x,21'-dihydroxy-16'13-methylpregna 1',3',5'- trien-3'-yloxy)-5a-androst-1-en-3-one in 5 ml. of anhydrous pyridine. To the dichloride thus formed 20 ml. of water is added at the rate that the reaction temperature does not exceed 10 C. The mixture is then allowed to remain at room temperature for 10 minutes and the pyridine is removed in vacuo 'WlthOllt applying external heat. The resulting residue is taken up in water, then sodium bicarbonate solution is carefully added until the mixture reaches pH 7. After extraction with chloroform, the aqueous phase is concentrated under vacuum to dryness. The residue is dissolved in methanol and the title compound precipitated by addition of 1:1 mixture of anhydrous ether and absolute ethanol.

4-en-3-one 21-disodium phosphate.

EXAMPLE 200 17,8-[ 17'13- (cyclohex-1"-enyloxy) -5a-androst-2-en-3 yloxy]-5a-androstan-3-one To an anhydrous boiling solution of 2.5 ml. cyclohexanone diethylketal and 20 mg. p-toluenesulfonic acid in 700 ml. benzene, 2 g. 17fi-(17'B-hydroxy-5'u-androst- 2'-en-3-yloxy)-5a-androstan-3-one (Ex. 184) was added and the mixture was heated with rapid solvent distillation for about 40 minutes. Then 1 ml. pyridine was added and the solvent completely removed under reduced pressure. The residue was taken up with methanol-ether, filtered and recrystallized from methylene chloride-methanol to give 1.7 g. -[17'B'-(cyclohex-1-eny1oxy) -5'aandrost-2-en-3'-yloxy] 5u-androstan-3-one, melting at 148-153 C. (dec.), [a] =+10 (c.=1%, dioxane).

In accordance with the above procedure the following disteroidyl ethers are obtained.

Preparation from- Product Ex. 184 and proplo- Product Ex. 189 and cyclo octanone dimethyl ketal.

We claim:

1. A disteroidyl ether consisting of two steroid moieties St and St, joined together by an oxygen atom linking the (i -position of steroid St with the C position of steriod St, wherein the steroid moiety St is selected from the group consisting of:

(1) An androstane, a 19-norandrostane and a 13-ethylgonane derivative of the 50cand Sit-series, optionally containing a single double bond between the carbon atoms in 1:2, 4:5 or 5:6 positions or two double bonds between the carbon atoms in 1:2 and 4:5 positions, said androstane, 19-norandrostane and 13- ethyl-gonane derivative having at the C -positin a substituent selected from the group consisting of hydrogen, a ketonic oxygen, and ocand fi-hydroxy group, and aand B-lower acyloxy group, an ester of said aand B-hydroxy group with a hydrocarbon dicarboxylic acid radical selected from the group consisting of hemisuccinyl and hemiphthalyl radicals, and a sulfate ester of said 02- and fi-hydroxy group;

and wherein the steroid moiety St is selected from the group consisting of:

(1) An androstane, a 19-norandrostane and a 13-ethylgonane derivative of the ozand SB-series, having an unsaturated structure selected from the group consisting of A -ene, A -ene, A -diene, and A -diene; having at the C -position a substituent selected from the group consisting of a hydrogen and a halogen atom; having at the C -position a substituent selected from the group consisting of hydrogen, a hydroxy group, and a methyl group; and having at the C position at least one substituent selected from the group consisting of a 17-keto group, a 17,3-hydroxy group, an ether of said 17B-hydroxy group with an alkenyl or cycloalkenyl radical containing from 4 to 8 carbon atoms, an ester of said l7B-hydroxy group with a hydrocarbon monocarboxylic acid radical containing up to 12 carbon atoms, an ester of said 173- hydroxy group with a hydrocarbon dicarboxylic acid radical selected from the group consisting of a hemisuccinyl and a hemiphthalyl radical; a sulfate or phosphate ester of said 17B-hydroxy group; a combination of a 17,8-hydroxy group together with a 17mlower alkyl, alkenyl or alkynyl group; a combination of an ester of said 17,3-hydroxy group with a hydrocarbon mono-carboxylic acid radical containing up to 12 carbon atoms, together with a l7oz-1OW6I alkyl, alkenyl or alkynyl group; a combination of an ester of said 17,9-hydroxy group with a hydrocarbon di-carboxylic acid radical selected from the group consisting of a hemisuccinyl and a hemiphthalyl radical, together with a 17a-lower alkyl, alkenyl or alkynyl group; a combination of a sulfate or phosphate ester of said 17/8-hydroxy group together with a 17-lower alkyl, alkenyl or al-kynyl group; and a 17- spirolactone group optionally coupled with a mercapto-acetate group in C -position; and

(2) A 20-ketopregnane of the 5aand S S-series, and a corresponding 19-nor derivative thereof, having an unsaturated structure selected from the group con sisting of A -ene, A -ene, A -diene, A -diene and -triene; having at the C -position a substituent selected from the group consisting of hydrogen, a methyl group, a chlorine and a fluorine atom; having at the C -position a substituent selected from the group consisting of hydrogen, fluoro and chloro; having at the C -position a substituent selected from the group consisting of hydrogen, a hydroxy group, a ketonic oxygen and a chlorine atom; having at the C -position a substituent selected from the group consisting of hydrogen, an u-hydroxy group, an ccmethyl group, a B-methyl group and a methylene group; having at the C -position a substituent selected from the group consisting of hydrogen, a hydroxy group and a lower acyloxy group containing up to 4 carbon atoms; and having at the C -position a substituent selected from the group consisting of hydrogen, a hydroXy group, an ester of said hydroxy group with a lower hydrocarbon mono-carboxylic acid radical, an ester of said hydroxy group with a hydrocarbon di-carboxylic acid radical selected from the group consisting of a hemisuccinyl, and a hemiphthalyl radical; and a sulfate or phosphate ester of said 2l-hydroxy group; said 20-ketopregnane derivative being also optionally substituted at the C and C -positions by a lower alkylidenedioxy group.

2. The process for preparing disteroidyl ethers according to claim 1 which comprises the step of reacting a 1719- hydroxy-steroid, selected from the group consisting of the androstane, 19-nor-androstane, gonane and 13-lower alkyl gonane series, with an enolized or acetalized 3-ketosteroid of the androstane and pregnane series and their 18-homo and 19-nor derivatives, under anhydrous conditions and in the presence of an acid catalyst selected from the group consisting of p-toluenesulfonic acid, naphthalenesulfonic acid, pyridine p-toluenesulfonate and pyridine chlorhydrate.

3. The process for preparing disteroidyl ethers according to claim 1 which comprises the step of reacting a 17- cycloalkenyl ether of a 17B-hydroxy steroid, selected from the group consisting of the androstane, l9-nor-androstane, gonane and 13-lower alkyl gonane series, with a S-ketosteroid of the androstane and pregnane series and their 18-homo and 19-nor derivatives, under anhydrous conditions and in the presence of an acid catalyst selected from the group consisting of p-toluenesulfonic acid, naphthalenesulfonic acid, pyridine p-toluenesulfonate and pyridine chlorhydrate.

4. Disteroidyl ethers of formula:

wherein:

R represents hydogen or methyl;

A represents hydrogen, an acyl radical containing up to 12 carbon atoms, a hemisuccinyl radical or a sulfate radical;

B represents hydrogen or an alkynyl radical containing up to 3 carbon atoms.

5. 1713 (171B propionoxyestra-3',5'-dien- -yloxy)- estr-4-en-3-one.

6. 175 (1773 hydr0xyestra-3',5-dien-3'-yloxy)-estr- 4-en-3-one.

7. 17B (l7fi lauryloxyestra-3,5-dien-3-yloxy)-estr- 4-en-3-one.

8. 17B (1773 acetoxy-19'-nor-17a-pregna-3',5'-dien- 20'-yn- '-yloxy)-estr-4-en-3-one.

9. 17;? (17'a acetoxy-20'-'oxo-6'-methylpregna-3',5'- dien- -yloxy)-estr-4-en-3-one.

10. 17B (20' oxo-19-norpregna-3',5'-dien- '-yloxy)- estr-4-en-3-one.

11. 1713 (l7;3 propionoxyandrosta 3',5'-dien-3'- yloXy)-estr-4-en-3-one.

12. 17 3 (17'6 hydroxyestra-3,5'-dien-3 -y1oxy)-estr- 4-en-3-one hemisuccinate.

13. 175 (1733 acetoxy s'a-androsta-l',3'-dien-3- yloxy)-5a-androst-1-en-3-one.

14. 17,8 (175 acetoxy 19'-nor-17'u-pregna-3',5'- dien-20'-yn- -yloxy)-androst--en-3fi-ol acetate.

15. 175 (1713 hydroxy 17'a-rnethylandrosta-3',5'- dien-3-yloxy)-androst-4-en-3-one.

16. 175 (17'5 acetoxy 19'-nor-17'a-pregna-3',5'- dien-20-3'-yloxy)-androst-4-en-3one.

17. 175 (9'0: fiuoro 11'6,17'a-dihydroxy-20'-oxo- 21' acetoxy 165 methylpregna-1',3',5'-trien-3'-yloxy)- estr-4-en-3-one.

18. 175 (1119,1751 dihydroxy-20'-oxo-21'-acetoxypregna-1',3 ,5'-trien-3'-yloxy) -estr-4-en-3-one.

19. 17B (17'a acetoXy-I9'-nor-20'-oxopregna-3,5- dien-3'-yloxy)-estr-4-en-3-one.

20. 17:! (17's hydroxy 17'a-ethylestra-3',5'-dien-3'- yloxy)-estr-4-en-3-one.

21. 17B (17'5 acetoxy-17'a-ethylestra-3',5'-dien-3'- yloxy)-estr-4-en-3-one.

22. 17B (9's fiuoro-l1'p,17'ot-dihydroxy-20'-oxo-2l'- acetoxy I613 methylpregna-3',5'-dien-3'-yloxy)-estr-4 en-3-one.

23. 17,6 (1713 acetOXy-Su-androst-2'en-3'-yloxy)- 5a-androst-1-ene-3-one.

24. 17B (1713 hydroxy 5'u-androst-2'-en-3' yloxy)- 5u-androst-1-en-3-one.

25. 17B (1713 hydroxyanclrosta-3',5'-dien-3'-y1oxy)- androst-4-en-3-one.

26. 17,6 (17'a acetoxy 20'oxopregna-3',5'-dien-3'- yloxy)-5a-androstan-3-one.

27. 175 (1718 hydroxyandrosta-3',5-dien-3'-yloxy)- androst-4-en-3-one hemisuccinate.

28. 17B (175 propionoxyestra-3',5'-dien- '-yloxy)- androst-4-en-3-one.

29. 17,8 (11,20 dioxo 17'u-hydroxy-21'-acetoxypregna-l,3', '-trien-3'-yloxy)-estr-4-en-3-one.

30. 173 (9-0: fluoro-17a-hydroxy-1l',20"-dioxo-2l'- acetoxy 16'5 methylpregna-1',3',5'-trien-3'-yloxy)-estr- 4-en-3-one.

31. 17B (9'0: fiuoro-l1,20"-dioxo-17'm,2l'-dihydroxy- 16'6 methylpregna 1',3',5'-trien-3'-yloxy)-estr-4-en-3- one.

32. 175 (9's: fluoro-l1',20-dioxo-l7'a-hydroxy21'- hemisuccinoxy 16'5 methylpregna-l,3',5'-trien-3'-yloxy)-estr-4-en-3-one.

33. 17B (1738 acetoxyestra-3',S'-dien-3'-yloxy)-estr- 4-en-3-one.

34. 175 (9'0: fiuoro-11'fl,l7a-dihydroxy-21'-acetoxy- 16'5 methylpregna 3',S' dien-3'-yloxy)-Su-androst-1- en-3-one.

35. Disteroidyl ethers of formula:

wherein the wavy line indicates that the hydrogen atom in 5 and 5' positions may have an a or ,6 configuration;

R represents a ketonic oxygen, an aor fl-hydroxy group, an aor fi-lower acyloxy group or an ester of said a and p-hydroxy groups with a hydrocarbon di-carboxylic acid radical selected from the group consisting of a hemisuccinyl and a. hemiphthalyl radical;

R and R each represent hydrogen or methyl;

R represents methyl or ethyl;

24 R represents hydrogen or hydroxy; X represents hydrogen or fluoro; the carbon atom at the C position having one of the following structures 36. In the process for preparing disteroidyl ethers according to claim 35 the step which comprises reacting a 17fi-hydroxy steroid of formula:

A B l 5 7.

wherein the wavy line in the 5-position and the substituents R and R are as defined in claim 42, the 1, 2, 6 and 7 positions are optionally substituted by a methyl radical or a halogen atom and the rings A and B optionally have one or two unsaturations, with an enolether or acetal of a 3- ketosteriod of formula:

wherein the wavy line in 5-position and the substituents R R R and X are as defined in claim 35, the carbon atom C has the structure where A and B are as defined in claim 35 with the exception that A is never hydrogen, the 1, 2', 6' and 7' positions are optionally substituted by a methyl radical or a halogen atom and the rings A and B of said 3-ketosteroid show one of the following structures:

said reaction being carried out under anhydrous conditions, in the presence of an acid catalyst selected from the group consisting of p-toluenesulfonic acid, naphthalenesulfonic acid, pyridine p-toluenesulfonate and pyridine chlorhydrate, and at temperatures between 50 and 200 C.

37. Disteroidyl ethers of formula:

wherein the wavy line indicates that the hydrogen atom in and 5' positions and the optional substituent in position 16 may have an at or B configuration;

R represents a ketonic oxygen, an 11- or p-hydroxy group,

an ocor fi-lower acyloxy group or an ester of said aand fl-hydroxy groups with a hydrocarbon di-carboxylic acid radical selected from the group consisting of hemisuccinyl and hemiphthalyl radicals;

R and R each represent hydrogen or methyl;

R represents hydrogen, fl-hydroxy, ketonic oxygen or chloro when also X represents chloro;

R represents hydrogen, a-hydroxy, a-methyl, fl-methyl or methylene;

R represents hydrogen, hydroxy or a lower acyloxy group containing up to 4 carbon atoms, inclusive;

R represents hydrogen, hydroxy, or an O-acyl group in which acyl is selected from the group consisting of a lower acyl radical, a hemisuccinyl, hemiphthalyl, a sulfate and a phosphate radical;

R and R may form together an isopropylidenedioxy radical or a 1'-methylbenzylidenedioxy radical;

X represents hydrogen, fluoro or chloro;

the rings A and B optionally being saturated or optionally having one unsaturation between the carbon atoms in 1:2,

4:5 or 5:6 positions or two unsaturations between the carbon atoms in 1:2 and 4:5 positions; the rings A and B having one of the following structures:

cording to claim 37 the step which comprises reacting a 17fl-hydroxysteroid of formula:

wherein the wavy line in the 5-position and the substituents R and R are as defined in claim 37, the 1, 2, 6 and 7 positions are optionally substituted by a methyl radical or a halogen atom and the rings A and B optionally have one or two unsaturations, with an enolether or acetal of a 3-ketosteroid of formula:

said reaction being carried out under anhydrous conditions, in the presence of an acid catalyst selected from the group consisting of p-toluenesulfonic acid, naphthalenesulfonic acid, pyridine p-toluenesulfonate and pyridine chlorhydrate, and at temperatures between 50 and 200 39. 4',5' dihydrospiro[3 (3" oxoestr-4"-en-17",8- yloxy) androsta 3,5-diene-17,2(34)-furane]-7u-thiol acetate.

40. 17B (17'fi propionoxyestra-B', -diene-3'-yloxy)- 5u-androst-2-ene.

No references cited.

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R. 

